lipid-a and Malaria--Falciparum

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; 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Pyridines; Pyrrolidines; Quality of Life; Quantum Dots; Quinoxalines; Quorum Sensing; Radiopharmaceuticals; Rain; Random Allocation; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Rats, Wistar; RAW 264.7 Cells; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, PAR-1; Receptors, CXCR4; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Interleukin-1; Receptors, Interleukin-17; Receptors, Notch; Recombinant Fusion Proteins; Recombinant Proteins; Reducing Agents; Reflex, Startle; Regional Blood Flow; Regression Analysis; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Tract Diseases; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Risk Assessment; Risk Factors; Rituximab; RNA, Messenger; RNA, Ribosomal, 16S; ROC Curve; Rosmarinic Acid; Running; Ruthenium; Rutin; Sarcolemma; Sarcoma; Sarcopenia; Sarcoplasmic Reticulum; SARS-CoV-2; Scavenger Receptors, Class A; Schools; Seasons; Seeds; Sequence Analysis, DNA; Severity of Illness Index; Sex Factors; Shock, Cardiogenic; Short Chain Dehydrogenase-Reductases; Signal Transduction; Silver; Singlet Oxygen; Sinusitis; Skin; Skin Absorption; Small Molecule Libraries; Smoke; Socioeconomic Factors; Soil; Soil Microbiology; Solid Phase Extraction; Solubility; Solvents; Spain; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Speech; Speech Perception; Spindle Poles; Spleen; Sporothrix; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Stomach Neoplasms; Stress, Physiological; Stroke Volume; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Rate; T-Lymphocytes, Cytotoxic; Tandem Mass Spectrometry; Temperature; Tenofovir; Terpenes; Tetracycline; Tetrapleura; Textiles; Thermodynamics; Thiobarbituric Acid Reactive Substances; Thrombin; Thyroid Hormones; Thyroid Neoplasms; Tibial Meniscus Injuries; Time Factors; 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The discovery and wide spread use of vaccines have saved millions of lives in the past few decades. Vaccine adjuvants represent an integral part of the modern vaccines. Despite numerous efforts, however, only a handful of vaccine adjuvants is currently available for human use. A comprehensive understanding of the mechanisms of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in mounting desirable immune responses to counter human pathogens. Decomposing the host response to vaccines and its components at systems level has recently been made possible owing to the recent advancements in Omics technology and cutting edge immunological assays powered by systems biology approaches. This approach has begun to shed light on the molecular signatures of several human vaccines and adjuvants. This review is an attempt to provide an overview of the recent efforts in systems analysis of vaccine adjuvants that are currently in clinic.

Topics: Adjuvants, Immunologic; alpha-Tocopherol; Animals; Drug Combinations; Glucosides; HIV Infections; Humans; Immunity, Innate; Immunogenicity, Vaccine; Influenza, Human; Lipid A; Liposomes; Malaria, Falciparum; Polysorbates; Squalene; Systems Analysis; Systems Biology; T-Lymphocytes, Helper-Inducer; Toll-Like Receptor 4; Vaccines

Numerous studies have demonstrated that most or all of the potent adjuvant activity of Gram-negative bacterial endotoxin resides in the lipid A moiety of lipopolysaccharide (LPS). Synthetic analogues of lipid A have provided insights into structure-activity relationships. Several cellular mechanisms of LPS and lipid A adjuvant activities have been identified. Activation of macrophages by LPS or lipid A results in cytokine secretions that enhance the immune response. LPS and lipid A cause recruitment of antigen-presenting cells, particularly macrophages. Liposomes containing lipid A serve as an in vivo adjuvant to recruit increased numbers of macrophages. Liposomal lipid A that has been phagocytized by cultured macrophages also serves as an "intracellular adjuvant" to cause increased immunologic presentation of liposomal antigen by the macrophages to specific T lymphocytes. Lipid A can abolish suppressor T cell activity, resulting in increased immune responses to polysaccharide antigens. Upon combination of lipid A or lipid A analogues with nonionic block polymers, modulation of murine antibody isotypes can be achieved with antibodies against a variety of antigens in vivo. Liposomes containing monophosphoryl lipid A (MPL) have been utilized in a phase I clinical trial of a proposed malaria vaccine in humans. The liposomal malaria vaccine resulted in very high levels of antibodies against the malarial antigen, and despite the presence of huge amounts of MPL (up to 2.2 mg), the liposomal lipid A was nonpyrogenic and safe for use in humans. Lipid A and lipid A analogues, and liposomes or other carriers containing lipid A, have shown considerable promise both as adjuvants for immunization of animals and for human vaccines.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Protozoan; Antigens, Protozoan; Drug Carriers; Gram-Negative Bacteria; Humans; Lipid A; Lipopolysaccharides; Liposomes; Malaria, Falciparum; Plasmodium falciparum; Vaccines, Synthetic

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; 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PRIMVAC is a VAR2CSA-derived placental malaria vaccine candidate aiming to prevent serious clinical outcomes of Plasmodium falciparum infection during pregnancy. We assessed the safety and immunogenicity of PRIMVAC adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) in French and Burkinabe women who were not pregnant.. This first-in-human, randomised, double-blind, placebo-controlled, dose escalation trial was done in two staggered phases, a phase 1A trial in 18-35-year-old women who were malaria naive in a hospital in France and a subsequent phase 1B trial in women who were naturally exposed to P falciparum and nulligravid in the clinical site of a research centre in Burkina Faso. Volunteers were recruited into four sequential cohorts receiving PRIMVAC intramuscularly at day 0, 28, and 56: two cohorts in France receiving 20 μg or 50 μg of PRIMVAC and then two in Burkina Faso receiving 50 μg or 100 μg of PRIMVAC. Volunteers were randomly assigned (1:1) to two groups (PRIMVAC adjuvanted with either Alhydrogel or GLA-SE) in France and randomly assigned (2:2:1) to three groups (PRIMVAC adjuvanted with either Alhydrogel, GLA-SE, or placebo) in Burkina Faso. Randomisation was centralised, using stratification by cohort and blocks of variable size, and syringes were masked by opaque labels. The primary endpoint was the proportion of participants with any grade 3 or higher adverse reaction to vaccination up until day 35. Safety at later time points as well as humoral and cellular immunogenicity were assessed in secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02658253.. Between April 19, 2016, and July 13, 2017, 68 women (18 in France, 50 in Burkina Faso) of 101 assessed for eligibility were included. No serious adverse event related to the vaccine occurred. PRIMVAC antibody titres increased with each dose and seroconversion was observed in all women vaccinated with PRIMVAC (n=57). PRIMVAC antibody titres reached a peak (geometric mean 11 843·0, optical density [OD] 1·0, 95% CI 7559·8-18 552·9 with 100 μg dose and GLA-SE) 1 week after the third vaccination (day 63). Compared with Alhydrogel, GLA-SE tended to improve the PRIMVAC antibody response (geometric mean 2163·5, OD 1·0, 95% CI 1315·7-3557·7 with 100 μg dose and Alhydrogel at day 63). 1 year after the last vaccination, 20 (71%) of 28 women who were vaccinated with PRIMVAC/Alhydrogel and 26 (93%) of 28 women who were vaccinated with PRIMVAC/GLA-SE still had anti-PRIMVAC antibodies, although antibody magnitude was markedly lower (452·4, OD 1·0, 95% CI 321·8-636·1 with 100 μg dose and GLA-SE). These antibodies reacted with native homologous VAR2CSA expressed by NF54-CSA infected erythrocytes (fold change from baseline at day 63 with 100 μg dose and GLA-SE: 10·74, 95% CI 8·36-13·79). Limited cross-recognition, restricted to sera collected from women that received the 100 μg PRIMVAC dose, was observed against heterologous VAR2CSA variants expressed by FCR3-CSA (fold change from baseline at day 63: 1·49, 95% CI 1·19-1·88) and 7G8-CSA infected erythrocytes (1·2, 1·08-1·34).. PRIMVAC adjuvanted with Alhydrogel or GLA-SE had an acceptable safety profile, was immunogenic, and induced functional antibodies reacting with the homologous VAR2CSA variant expressed by NF54-CSA infected erythrocytes. Cross-reactivity against heterologous VAR2CSA variants was limited and only observed in the higher dose group. An alternate schedule of immunisation, antigen dose, and combinations with other VAR2CSA-based vaccines are envisaged to improve the cross-reactivity against heterologous VAR2CSA variants.. Bundesministerium für Bildung und Forschung, through Kreditanstalt für Wiederaufbau, Germany; Inserm, and Institut National de Transfusion Sanguine, France; Irish Aid, Department of Foreign Affairs and Trade, Ireland.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibody Formation; Burkina Faso; Double-Blind Method; Female; France; Glucosides; Humans; Immunization; Immunogenicity, Vaccine; Lipid A; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Vaccination; Young Adult

P27A is an unstructured 104mer synthetic peptide from Plasmodium falciparum trophozoite exported protein 1 (TEX1), the target of human antibodies inhibiting parasite growth. The present project aimed at evaluating the safety and immunogenicity of P27A peptide vaccine in malaria-nonexposed European and malaria-exposed African adults.. This study was designed as a staggered, fast-track, randomized, antigen and adjuvant dose-finding, multicenter phase 1a/1b trial, conducted in Switzerland and Tanzania. P27A antigen (10 or 50 μg), adjuvanted with Alhydrogel or glucopyranosil lipid adjuvant stable emulsion (GLA-SE; 2.5 or 5 μg), or control rabies vaccine (Verorab) were administered intramuscularly to 16 malaria-nonexposed and 40 malaria-exposed subjects on days 0, 28, and 56. Local and systemic adverse events (AEs) as well as humoral and cellular immune responses were assessed after each injection and during the 34-week follow-up.. Most AEs were mild to moderate and resolved completely within 48 hours. Systemic AEs were more frequent in the formulation with alum as compared to GLA-SE, whereas local AEs were more frequent after GLA-SE. No serious AEs occurred. Supported by a mixed Th1/Th2 cell-mediated immunity, P27A induced a marked specific antibody response able to recognize TEX1 in infected erythrocytes and to inhibit parasite growth through an antibody-dependent cellular inhibition mechanism. Incidence of AEs and antibody responses were significantly lower in malaria-exposed Tanzanian subjects than in nonexposed European subjects.. The candidate vaccine P27A was safe and induced a particularly robust immunogenic response in combination with GLA-SE. This formulation should be considered for future efficacy trials.. NCT01949909, PACTR201310000683408.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibodies, Protozoan; Drug-Related Side Effects and Adverse Reactions; Female; Glucosides; Healthy Volunteers; Humans; Injections, Intramuscular; Lipid A; Malaria Vaccines; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Switzerland; Tanzania; Vaccines, Synthetic; Young Adult

In an attempt to improve the efficacy of the candidate malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum thrombospondin-related anonymous protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination vaccine had an acceptable safety profile and was acceptably tolerated. Antigen-specific antibodies, lymphoproliferative responses, and IFN-γ production by ELISPOT assay elicited with the combination vaccine were qualitatively similar to those generated by the single component vaccines. However, post-dose 2 anti-CS antibodies in the RTS,S+TRAP/AS02 vaccine recipients were lower than in the RTS,S/AS02 vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate vaccine. The absence of significant protection or delay of parasitemia in the 11 RTS,S+TRAP/AS02 vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP antigen may have interfered with the vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based vaccines should consider employing alternative vaccine platforms.

Topics: Adolescent; Adult; Antibodies, Protozoan; Antigens, Protozoan; Cell Proliferation; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Enzyme-Linked Immunospot Assay; Female; Humans; Interferon-gamma; Leukocytes, Mononuclear; Lipid A; Malaria Vaccines; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Protozoan Proteins; Saponins; Treatment Outcome; Vaccination; Young Adult

This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems.. After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 microg/0.5 mL) of AMA-1/AS01B (n = 15) or AMA-1/AS02A (n = 15), followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs) with 95% Confidence Intervals (CIs) were high: low dose AMA-1/AS01B 196 microg/mL (103-371 microg/mL), full dose AMA-1/AS01B 279 microg/mL (210-369 microg/mL) and full dose AMA-1/AS02A 216 microg/mL (169-276 microg/mL) with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA), against homologous but not against heterologous (FVO) parasites as well as demonstrable interferon-gamma (IFN-gamma) responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR). However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements.. All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite growth rates from qPCR data may suggest a partial biological effect of the vaccine. Further evaluation of the immunogenicity and efficacy of the AMA-1/AS02A formulation is ongoing in a malaria-experienced pediatric population in Mali.. www.clinicaltrials.gov NCT00385047.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Alleles; Animals; Antigens, Protozoan; Double-Blind Method; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Humans; Lipid A; Malaria Vaccines; Malaria, Falciparum; Membrane Proteins; Middle Aged; Plasmodium falciparum; Protozoan Proteins; Saponins

We report the first trial of candidate malaria vaccine antigen FMP1, a 42kDa fragment from the C-terminus of merozoite surface protein-1 (MSP-1) from the 3D7 strain of Plasmodium falciparum, in an endemic area. Forty adult male and female residents of western Kenya were enrolled to receive 3 doses of either FMP1/AS02A or Imovax rabies vaccine by intra-deltoid injection on a 0, 1, 2 month schedule. Thirty-seven volunteers received all three immunizations and 38 completed the 12-month evaluation period. Slightly more recipients of the FMP1/AS02A vaccine experienced any instance of pain at 24 h post-immunization than in the Imovax group (95% versus 65%), but otherwise the two vaccines were equally safe and well-tolerated. Baseline antibody levels were high in both groups and were boosted in the FMP1/AS02A group. Longitudinal models revealed a highly significant difference between groups for both the average post-baseline antibody responses to MSP-1(42) (F1,335=13.16; P<0.001) and the Day 90 responses to MSP-1(42) (F1,335=16.69; P<0.001). The FMP1/AS02A vaccine is safe and immunogenic in adults and should progress to safety testing in children at greatest risk of malaria.

Topics: Adjuvants, Immunologic; Adult; Animals; Antibodies, Protozoan; Double-Blind Method; Drug Combinations; Female; Humans; Kenya; Lipid A; Malaria Vaccines; Malaria, Falciparum; Male; Merozoite Surface Protein 1; Middle Aged; Plasmodium falciparum; Saponins; Treatment Outcome

A Plasmodium falciparum circumsporozoite protein (PfCSP) recombinant fusion protein, R32NS1(81), formulated with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane (Detox) was administered to 12 volunteers. One volunteer had malaise and self-limited painful induration at the injection site after the second dose and declined further immunization. The other 11 volunteers tolerated the three doses of 1,230 micrograms of vaccine, but most complained of sore arms; in five cases the pain or malaise was severe enough to interfere with work or sleep. Two weeks after the third dose of vaccine, four of the 11 immunized volunteers had > or = 14 micrograms/ml of antibodies to the repeat region of the PfCSP in their serum. Two of these four volunteers did not develop P. falciparum parasitemia when challenged by the bite of five mosquitoes carrying P. falciparum sporozoites. The seven volunteers with lower levels of antibodies and 11 of 11 controls developed parasitemia. These data are consistent with other studies, and indicate that vaccine-induced antibodies against the repeat region of PfCSP can prevent effective sporozoite infection of hepatocytes in humans. The challenge is to improve the immunogenicity of PfCSP-based vaccines, and to develop methods for including PfCSP peptides as components of multitarget malaria vaccines.

Topics: Adjuvants, Immunologic; Adult; Amino Acid Sequence; Animals; Antibodies, Protozoan; Cell Wall; Double-Blind Method; Humans; Lipid A; Malaria Vaccines; Malaria, Falciparum; Middle Aged; Military Personnel; Molecular Sequence Data; Mycobacterium phlei; Parasitemia; Plasmodium falciparum; Protozoan Proteins; Safety; Squalene; United States; Vaccines, Synthetic

Plasmodium falciparum cysteine-rich protective antigen (PfCyRPA) is an invasion complex protein essential for erythrocyte invasion. In contrast to several previously clinically tested merozoite vaccine candidate antigens, PfCyRPA is not polymorphic, making it a promising candidate antigen for blood stage vaccine development.. Mice and rabbits were immunized with vaccine formulations of recombinantly expressed PfCyRPA adjuvanted either with the glucopyranosyl lipid A (GLA) containing adjuvants GLA-LSQ, GLA-SE, GLA-Alum or with Nanoalum. ELISA and indirect immunofluorescence assays (IFA) were used to analyse elicited IgG titers and the P. falciparum growth inhibitory activity was determined with a standardized in vitro [. In the mouse experiments, the GLA adjuvanted formulations were superior to the Nanoalum formulation with respect to antibody titer development, IFA sero-conversion rates and in vitro parasite growth-inhibitory activity. In rabbits, the highest titers of parasite growth inhibitory antibodies were obtained with the GLA-SE formulation. Comparable mean ELISA IgG endpoint titers were reached in rabbits after three immunizations with GLA-SE adjuvanted PfCyRPA doses of 5, 25 and 100 µg, but with 100 µg of antigen, only two immunizations were required to reach this titer.. PfCyRPA formulated with the human-compatible adjuvant GLA-SE represents an attractive vaccine candidate for early clinical testing in a controlled P. falciparum blood stage challenge trial.

Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Animals; Animals, Laboratory; Antibodies, Protozoan; Antigens, Protozoan; Humans; Immunoglobulin G; Lipid A; Malaria Vaccines; Malaria, Falciparum; Mice; Parasites; Plasmodium falciparum; Protozoan Proteins; Rabbits; Toll-Like Receptor 4

The Plasmodium falciparum sexual-stage surface proteins Pfs25 and Pfs230 are antigen candidates for a malaria transmission-blocking vaccine (TBV), and have been widely investigated as such. It is not clear whether simultaneously presenting these two antigens in a particulate vaccine would enhance the transmission reducing activity (TRA) of induced antibodies. To assess this, immunization was carried out with liposomes containing synthetic lipid adjuvant monophosphoryl lipid A (MPLA), and cobalt-porphyrin-phospholipid (CoPoP), which rapidly converts recombinant, his-tagged antigens into particles.. His-tagged, recombinant Pfs25 and Pfs230C1 were mixed with CoPoP liposomes to form a bivalent vaccine. Antigens were fluorescently labelled to infer duplex particleization serum-stability and binding kinetics using fluorescence resonance energy transfer. Mice and rabbits were immunized with individual or duplexed particleized Pfs25 and Pfs230C1, at fixed total antigen doses. The resulting antibody responses were assessed for magnitude and TRA.. Pfs230C1 and Pfs25 rapidly bound CoPoP liposomes to form a serum-stable, bivalent particle vaccine. In mice, immunization with 5 ng of total antigen (individual antigen or duplexed) elicited functional antibodies against Pfs25 and Pfs230. Compared to immunization with the individual antigen, Pfs25 antibody production was moderately lower for the bivalent CoPoP vaccine, whereas Pfs230C1 antibody production was not impacted. All antibodies demonstrated at least 92% inhibition in oocyst density at 750 μg/mL purified mouse IgG in the standard membrane feeding assay (SMFA). At lower IgG concentrations, the bivalent vaccine did not improve TRA; antibodies induced by particleized Pfs25 alone showed stronger function in these conditions. In rabbits, immunization with a 20 µg total antigen dose with the duplexed antigens yielded similar antibody production against Pfs25 and Pfs230 compared to immunization with a 20 µg dose of individual antigens. However, no enhanced TRA was observed with duplexing.. Pfs25, Pfs230 or the duplexed combination can readily be prepared as particulate vaccines by mixing CoPoP liposomes with soluble, recombinant antigens. This approach induces potent transmission-reducing antibodies following immunization in mice and rabbits. Immunization with bivalent, particleized, Pfs230 and Pfs25 did not yield antibodies with superior TRA compared to immunization with particleized Pfs25 as a single antigen. Altogether, duplexing antigens is straightforward and effective using CoPoP liposomes, but is likely to be more useful for targeting distinct parasite life stages.

Topics: Adjuvants, Immunologic; Animals; Female; Immunization; Injections, Intramuscular; Lipid A; Liposomes; Malaria Vaccines; Malaria, Falciparum; Mice; Rabbits

Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD®). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-γ ELISPOT activity, CD4

Topics: Adjuvants, Immunologic; Animals; Antibodies, Protozoan; B-Lymphocytes; CD4-Positive T-Lymphocytes; Disease Models, Animal; Enzyme-Linked Immunospot Assay; Female; Interferon-gamma; Lipid A; Liposomes; Malaria Vaccines; Malaria, Falciparum; Mice, Inbred C57BL; Protozoan Proteins; Saponins

Plasmodium falciparum is transmitted from person to person by Anopheles mosquitoes after completing its sexual reproductive cycle within the infected mosquito. An efficacious vaccine holds the potential to interrupt development of the parasite in the mosquito leading to control and possibly eradication of malaria. A multi-component, R0.10C, was developed comprising P. falciparum glutamate-rich protein (R0) fused in frame to a correctly folded fragment of Pfs48/45 (10C). Here, a series of novel adjuvants were screened for their ability to elicit transmission-blocking (TB) antibodies.. The recombinant fusion protein R0.10C was produced in Lactococcus lactis and purified by affinity-chromatography on a monoclonal antibody (mAb 85RF45.1) against a major epitope for TB antibodies (epitope 1) harboured on R0.10C. Immune-purified R0.10C was mixed with a series of adjuvants and tested in mice and rats.. In general, all R0.10C formulations elicited high levels of antibodies recognizing native Pfs48/45 in macrogametes/zygotes. TB activity of anti-R0.10C antisera was assessed in the standard membrane-feeding assay (SMFA). Potency of different adjuvant/R0.10C combinations was tested in mice and rats using aluminium hydroxide (Alum), Alum with micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA), stable emulsion (SE)/GLA, AbISCO-100 and Freund's adjuvant (as reference). All formulations produced high antibody titres recognizing the native Pfs48/45 protein in macrogametes/zygotes. Interestingly, the GLA-Alum combination adjuvant was the most potent inducer of TB antibodies based on serum collected after two immunizations. In agreement with previous observations, biological activity in the SMFA correlated well with the level of anti-Pfs48/45 antibodies.. The combined data provide a strong basis for entering the next phase of clinical grade R0.10C production and testing.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Antibodies, Protozoan; Emulsions; Female; Glucosides; Immunoglobulin G; Lipid A; Malaria, Falciparum; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Plasmodium falciparum; Protozoan Proteins; Protozoan Vaccines; Rats; Rats, Wistar; Recombinant Fusion Proteins; Saponins

Immunizations with Plasmodium falciparum MSP1-42 or MSP1-19 induce antibodies that inhibit parasites in vitro, which correlates with in vivo protective immunity by vaccination. We previously showed that several adjuvant formulations can induce anti-MSP1-19 antibodies in interleukin-6, intercellular adhesion molecule 1, CD80, and CD86 knockout (KO) mice and at levels similar to those obtained in the healthy uninfected hosts. Here, we determine whether these immune gene KOs or the immunopotentiating activities of the adjuvants have a more important influence on the induction of parasite-inhibitory anti-MSP1-19 antibodies. Results showed that the biological activities of the anti-MSP1-19 antibodies induced by these adjuvants were not affected by the immune gene KOs. All adjuvant formulations that induced significant inhibitory antibody responses (i.e., >50% inhibition of parasite growth) contained monophosphoryl lipid A (MPL) in emulsion carriers, whereas MPL or emulsion carriers alone were ineffective. The ability to retain vaccine efficacy by the MSP1-19 and adjuvant formulations in the altered immunological background is a valuable and significant attribute in light of many instances of skewed immune status in the targeted vaccine populations.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Protozoan; Emulsions; Immunization; Lipid A; Malaria Vaccines; Malaria, Falciparum; Merozoite Surface Protein 1; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Plasmodium falciparum

Several lines of evidence suggest that targeting pre-erythrocytic-stage parasites for malaria vaccine development can provide sterile immunity. The objectives of this study were (i) to evaluate preclinically the safety and immunogenicity of a new recombinant pre-erythrocytic-stage antigen, liver-stage antigen 1 (LSA1), in nonhuman primates; and (ii) to investigate the potential for immune interference between LSA1 and the leading malaria vaccine candidate, RTS,S, by comparing the immune responses after single-antigen vaccination to responses after simultaneous administration of both antigens at separate sites. Using a rhesus monkey model, we found that LSA1 formulated with the GlaxoSmithKline proprietary adjuvant system AS01B (LSA1/AS01B) was safe and immunogenic, inducing high titers of antigen-specific antibody and CD4+ T-cell responses, as monitored by the production of interleukin-2 and gamma interferon, using intracellular cytokine staining. RTS,S/AS01B vaccination was well tolerated and demonstrated robust antibody and moderate CD4+ T-cell responses to circumsporozoite protein (CSP) and HBsAg. Positive CD8+ T-cell responses to HBsAg were detected, whereas the responses to CSP and LSA1 were negligible. For both LSA1/AS01B and RTS,S/AS01B, no statistically significant differences were observed between individual and concurrent administration in the magnitude or duration of antibody and T-cell responses. Our results revealed that both pre-erythrocytic-stage antigens were safe and immunogenic, administered either separately or simultaneously to rhesus monkeys, and that no significant immune cross interference occurred with concurrent separate-site administration. The comparison of the profiles of immune responses induced by separate-site and single-site vaccinations with LSA1 and RTS,S warrants further investigation.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Protozoan; Antigens, Protozoan; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Lipid A; Macaca mulatta; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Saponins; Time Factors

A vaccine trial was conducted to determine the efficacy of a multicomponent candidate vaccine, FALVAC-1, against Plasmodium falciparum in Aotus nancymai monkeys. After two immunizations, animals were challenged intravenously with parasites of the Vietnam Oak Knoll (FVO) strain of P. falciparum. The primary outcome was to determine the protective response of the monkeys to immunization with the FALVAC-1 antigen produced in baculovirus when combined with different adjuvants (alum, QS-21, ASO2a, CRL1005/oil, and CRL1005/saline) as compared with FALVAC-1 with FCA/FIA and antigen alone. When compared with the monkeys immunized with FALVAC-1 alone, FALVAC-1 with FCA/FIA reduced the mean parasite count (to Day 11), reduced the mean accumulated parasitemia (through Day 11), and extended the number of days to treatment. None of the other 5 antigen-adjuvant combinations were able to provide discernable levels of protection based on log(parasitemia) and log(cumulative parasitemia) to Day 11.

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Aotidae; Disease Models, Animal; Drug Combinations; Female; Freund's Adjuvant; Hematocrit; Immunization Schedule; Lipid A; Malaria Vaccines; Malaria, Falciparum; Male; Plasmodium falciparum; Polymers; Saponins; Treatment Outcome; Vaccines, Synthetic

Encapsulation of soluble protein antigens in liposomes was previously shown to result in processing of antigen via the major histocompatibility complex class I pathway, as evidenced by costaining of the trans-Golgi region of murine bone marrow-derived macrophages (BMs) by fluorophore-labeled liposomal antigen and by a trans-Golgi-specific fluorescent lipid. Evidence is presented here that free or liposome-encapsulated RTS,S, a particulate malaria antigen consisting of hepatitis B particles coexpressed with epitopes from the Plasmodium falciparum circumsporozoite protein, also was localized in the trans-Golgi after incubation with BMs, suggesting processing by the class I pathway. An in vivo cytotoxic T-lymphocyte (CTL) response was detected, however, only after immunization with RTS,S encapsulated in liposomes containing lipid A and not after immunization with free RTS,S or with RTS,S encapsulated in liposomes lacking lipid A. Therefore, intracellular delivery of antigen containing CTL epitopes to the Golgi of BMs does not necessarily result in a CTL response in vivo unless an additional adjuvant, such as liposomes containing lipid A, is utilized. Encapsulation of RTS,S in liposomes containing monophosphoryl lipid A (MPL) resulted in a dose-dependent enhancement of the NANP-specific immunoglobulin G (IgG) antibody response compared to that of free RTS,S. The IgG1 and IgG2a subclasses predominated after immunization with RTS,S encapsulated in liposomes containing MPL. These results demonstrate that encapsulation of a lipid-containing particulate antigen, such as RTS, S, in liposomes containing lipid A can enhance both humoral and cellular immune responses.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Protozoan; Antigens, Protozoan; Bone Marrow Cells; Cytotoxicity, Immunologic; Drug Carriers; Hepatitis B Surface Antigens; Immunoglobulin G; Lipid A; Liposomes; Macrophages; Malaria, Falciparum; Peptide Fragments; Plasmodium falciparum; Protozoan Proteins; T-Lymphocytes, Cytotoxic; Vaccination